Dataset Information

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

ABSTRACT: Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored.To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons.Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies.The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss.Parkinson disease risk alleles in the MAPT (rs2942168; P?=?.0006) and CCDC62 (rs12817488; P?=?.004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P?=?.0002) and CCDC62 (P?=?.003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P?=?.005) and gait impairment, SNCA (rs356220; P?=?.04) and rigidity, and GAK (rs1564282; P?=?.03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P?=?.03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies.In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

SUBMITTER: Shulman JM

PROVIDER: S-EPMC4039209 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

Shulman Joshua M JM Yu Lei L Buchman Aron S AS Evans Denis A DA Schneider Julie A JA Bennett David A DA De Jager Philip L PL

JAMA neurology 20140401 4

<h4>Importance</h4>Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored.<h4>Objective</h4>To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons.<h4>Design, setting, and participants</h4>Eighteen candidate single-nu ...[more]

PMID: 24514572

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Project description:ImportanceBrain atrophy and vascular lesions contribute to dementia and mild cognitive impairment (MCI) in clinical referral populations. Prospective evidence in older general populations is limited.ObjectiveTo evaluate which magnetic resonance imaging (MRI) signs are independent risk factors for dementia and MCI.Design, setting, and participantsThis population-based cohort study included 1553 participants sampled from the Atherosclerosis Risk in Communities Study who had brain MRI scans and were dementia free during visit 5 (June 2011 to September 2013). Participants' cognitive status was evaluated through visit 6 (June 2016 to December 2017).ExposuresBrain regional volumes, microhemorrhages, white matter hyperintensity (WMH) volumes, and infarcts measured on 3-T MRI.Main outcomes and measuresCognitive status (dementia, MCI, or nonimpaired cognition) was determined from in-person evaluations. Dementia among participants who missed visit 6 was identified via dementia surveillance and hospital discharge or death certificate codes. Cox proportional hazards models were used to evaluate the risk of dementia in 3 populations: dementia-free participants (N = 1553), participants with nonimpaired cognition (n = 1014), and participants with MCI (n = 539). Complementary log-log models were used for risk of MCI among participants with nonimpaired cognition who also attended visit 6 (n = 767). Models were adjusted for demographic variables, apolipoprotein E ε4 alleles, vascular risk factors, depressive symptoms, and heart failure.ResultsOverall, 212 incident dementia cases were identified among 1553 participants (mean [SD] age at visit 5, 76 [5.2] years; 946 [60.9%] women; 436 [28.1%] African American) with a median (interquartile range) follow-up period of 4.9 (4.3-5.2) years. Significant risk factors of dementia included lower volumes in the Alzheimer disease (AD) signature region, including hippocampus, entorhinal cortex, and surrounding structures (hazard ratio [HR] per 1-SD decrease, 2.40; 95% CI, 1.89-3.04), lobar microhemorrhages (HR, 1.90; 95% CI, 1.30-2.77), higher volumes of WMH (HR per 1-SD increase, 1.44; 95% CI, 1.23-1.69), and lacunar infarcts (HR, 1.66; 95% CI, 1.20-2.31). The AD signature region volume was also consistently associated with both MCI and progression from MCI to dementia, while subcortical microhemorrhages and infarcts contributed less to the progression from MCI to dementia.Conclusions and relevanceIn this study, lower AD signature region volumes, brain microhemorrhages, higher WMH volumes, and infarcts were risk factors associated with dementia in older community-based residents. Vascular changes were more important in the development of MCI than in its progression to dementia, while AD-related signs were important in both stages.

Project description:ImportanceLarge-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian).ObjectivesTo identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.Design setting, and participantsGenome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria.Main outcomes and measuresGenotypes of common variants, association with disease status, and polygenic risk scores.ResultsOf 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12).Conclusions and relevanceThis study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

Dataset Information

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

Publications

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

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